1972-08-3

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In this contribution, a comprehensive study of the redox transformation, electronic structure, stability and photoprotective properties of phytocannabinoids is presented. The non-psychotropic cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), and psychotropic tetrahydrocannabinol (THC) isomers and iso-THC were included in the study. The results show that under aqueous ambient conditions at pH 7.4, non-psychotropic cannabinoids are slight or moderate electron-donors and they are relatively stable, in the following order: CBD > CBG ≥ CBN > CBC. In contrast, psychotropic Δ9-THC degrades approximately one order of magnitude faster than CBD. The degradation (oxidation) is associated with the transformation of OH groups and changes in the double-bond system of the investigated molecules. The satisfactory stability of cannabinoids is associated with the fact that their OH groups are fully protonated at pH 7.4 (pKa is ≥ 9). The instability of CBN and CBC was accelerated after exposure to UVA radiation, with CBD (or CBG) being stable for up to 24 h. To support their topical applications, an in vitro dermatological comparative study of cytotoxic, phototoxic and UVA or UVB photoprotective effects using normal human dermal fibroblasts (NHDF) and keratinocytes (HaCaT) was done. NHDF are approx. twice as sensitive to the cannabinoids’ toxicity as HaCaT. Specifically, toxicity IC50 values for CBD after 24 h of incubation are 7.1 and 12.8 μM for NHDF and HaCaT, respectively. None of the studied cannabinoids were phototoxic. Extensive testing has shown that CBD is the most effective protectant against UVA radiation of the studied cannabinoids. For UVB radiation, CBN was the most effective. The results acquired could be used for further redox biology studies on phytocannabinoids and evaluations of their mechanism of action at the molecular level. Furthermore, the UVA and UVB photoprotectivity of phytocannabinoids could also be utilized in the development of new cannabinoid-based topical preparations.

A two-step synthesis of para (-)-Δ8-THC-OTf that can be used as building block for late-stage introduction of side chains to the tetrahydrodibenzopyran core of THC by cross-coupling chemistry is presented. No protecting groups are needed, and (

Efficient tetrahydrocannabinol (Δ9-THC) production from cannabis is important for its medical application and as basis for the development of production routes of other drugs from plants. This work presents one of the steps of Δ9-THC production from cannabis plant material, the decarboxylation reaction, transforming the Δ9- THC-acid naturally present in the plant into the psychoactive Δ9-THC. Results of experiments showed pseudo-first order reaction kinetics, with an activation barrier of 85 kJ mol-1 and a pre-exponential factor of 3.7 × 108 s-1. Using molecular modeling, two options were identified for an acid catalyzed β-keto acid type mechanism for the decarboxylation of Δ9- THC-acid. Each of these mechanisms might play a role, depending on the actual process conditions. Formic acid proved to be a good model for a catalyst of such a reaction. Also, the computational idea of catalysis by water to catalysis by an acid, put forward by Li and Brill, and Churchev and Belbruno was extended, and a new direct keto-enol route was found. A direct keto-enol mechanism catalyzed by formic acid seems to be the best explanation for the observed activation barrier and the pre-exponential factor of the decarboxylation of Δ9-THC-acid. Evidence for this was found by performing an extraction experiment with Cannabis Flos. It revealed the presence of short chain carboxylic acids supporting this hypothesis. The presented approach is important for the development of a sustainable production of Δ9-THC from the plant.

The chemical reactivity of cannabidiol is based on its ability to undergo intramolecular cyclization driven by the addition of a phenolic group to one of its two double bonds. The main products of this cyclization are Δ9-THC (trans-Δ-9-tetrahydrocannabinol) and Δ8-THC (trans-Δ-8-tetrahydrocannabinol). These two cannabinoids are isomers, and the first one is a frequently investigated psychoactive compound and pharmaceutical agent. The isomers Δ8-iso-THC (trans-Δ-8-iso-tetrahydrocannabinol) and Δ4(8)-iso-THC (trans-Δ-4,8-iso-tetrahydrocannabinol) have been identified as additional products of intramolecular cyclization. The use of Lewis and protic acids in different solvents has been studied to investigate the possible modulation of the reactivity of CBD (cannabidiol). The complete NMR spectroscopic characterizations of the four isomers are reported. High-performance liquid chromatography analysis and 1H NMR spectra of the reaction mixture were used to assess the percentage ratio of the compounds formed.

A process of converting cannabidiol (CBD) to Δ8-tetrahydrocannabinol (Δ8-THC) or Δ9-tetrahydrocannabinol (Δ9-THC) can enable mass production of Δ8-THC and/or Δ9-THC, achieve greater yields and higher purity in comparison to previously reported processes while eliminating the use of organic solvent. The resultant hemp-derived Δ8-THC can be mixed with and absorbed by natural extracts, including tea extract, starch, sugar, lecithin, and other emulsifiers. Δ8-THC used in edible, topical and vaping products such as powdered Δ8-THC food ingredients, tablets or pills, suppositories, and vape formulations are disclosed. Further described are beverages and baked goods utilizing or incorporating the tablets or powdered Δ8-THC to create edible products containing an emulsified, tasteless, and odorless dose of Δ8-THC. The disclosure also describes a rectal suppository designed to provide improved comfort of use. A Δ8-THC liquid composition can be use in an electronic cigarette smoking device for pulmonary administration of Δ8-THC, which results in more effective absorption.

This disclosure provides a method for converting CBD to a tetrahydrocannabinol featuring the use of cheap and non-toxic aluminum isopropoxide as a catalyst. The method comprises (a) providing a reaction mixture comprising a catalyst in an organic solvent, wherein the catalyst comprises aluminum isopropoxide; (b) adding a reagent comprising CBD to the reaction mixture; (c) mixing the reaction mixture and allowing a reaction for converting CBD to a tetrahydrocannabinol to occur for a predetermine period of time; (d) removing the catalyst by filtration upon the completion of the reaction; (e) removing the organic solvent; and (f) eluting the tetrahydrocannabinol from the organic phase.

Methods and instrumentation for converting cannabidiol (CBD) and CBD-like compounds to other naturally-occurring or synthetic cannabinoids, such as THC, CBN and/or CBC, which processes may be solvent-free, Generally, the conversion of CBD is carried out in the presence of a Lewis acid, an oxidant or both, which may be present in catalytic amounts. A reaction may be a two-phase reaction with the Lewis acid present on a support material in a column or similar chamber through which CBD passes and is converted to the cannabinoids. The reactions allow direction of relative yields of certain cannabinoid products by altering the identity of the acid reagent.

A method of converting cannabidiol (CBD) into Δ9-Tetrahydrocannabinol (Δ9-THC) and Δ8-Tetrahydrocannabinol (Δ8-THC). The method provides a polar aprotic solvent such as Tert-Butyl Methyl Ether, Tetrahydrofuran, dicloromethane, or chloroform. Cannabidiol starting material mixes into the polar aprotic solvent in a chemical reactor to make a cannabinoid solution. Adding a metallic catalyst capable of performing intramolecular hydroalkoxylation to the cannabinoid solution and mixing it converts the cannabidiol starting material into Δ9-Tetrahydrocannabinol (Δ9-THC) and Δ8-Tetrahydrocannabinol (Δ8-THC) in a ratio of at least 6:1. The catalyst is a metal such as a transition metal or is selected from the group consisting of ruthenium, aluminum, iron, gold, silver, copper, platinum, and combinations thereof. In one embodiment a co-catalyst is used such as a triflate salt. Regulating the temperature of the reaction to less than 20° C. yields a predominance of Δ9-THC, i.e. Δ9-THC is more than 75% of the cannabinoid mix.

Thecis-stereoisomers of Δ9-THC [(?)- 3 and (+)- 3 ] were identified and quantified in a series of low-THC-containing varieties ofCannabis sativaregistered in Europe as fiber hemp and in research accessions of cannabis. While Δ9-cis-THC ( 3 ) occurs in cannabis fiber hemp in the concentration range of (?)-Δ9-trans-THC [(?)- 1 ], it was undetectable in a sample of high-THC-containing medicinal cannabis. Natural Δ9-cis-THC ( 3 ) is scalemic (ca. 80-90% enantiomeric purity), and the absolute configuration of the major enantiomer was established as 6aS,10aR[(?)- 3 ] by chiral chromatographic comparison with a sample available by asymmetric synthesis. The major enantiomer, (?)-Δ9-cis-THC [(?)- 3 ], was characterized as a partial cannabinoid agonist in vitro and elicited a full tetrad response in mice at 50 mg/kg doses. The current legal discrimination between narcotic and non-narcotic cannabis varieties centers on the contents of “Δ9-THC and isomers” and needs therefore revision, or at least a more specific wording, to account for the presence of Δ9-cis-THCs [(+)- 3 and (?)- 3 ] in cannabis fiber hemp varieties.

The present invention relates to a tetrahydrocannabinol (THC) type cannabinoid compound for use as a medicament. The THC-type cannabinoid is an enantiomer of the (-)-trans- tetrahydrocannabinol which is a naturally occurring cannabinoid that can be found in cannabis plant strains which have been bred to yield THC as the dominant cannabinoid. The particular enantiomer (+)-cis tetrahydrocannabinol has been found to have properties which are different from the naturally occurring (-)-trans-THC. The cannabinoid (+)-cis-THC has been found to occur in low concentrations in particular cannabis plant strains which have been bred to produce cannabidiol (CBD) as the dominant cannabinoid. Furthermore, the cannabinoid can be produced by synthetic means.

The present invention relates to a tetrahydrocannabinol (THC) type cannabinoid compound for use as a medicament. The THC-type cannabinoid is an enantiomer of the (-)-trans- tetrahydrocannabinol which is a naturally occurring cannabinoid that can be found in cannabis plant strains which have been bred to yield THC as the dominant cannabinoid. The particular enantiomer (-)-cis tetrahydrocannabinol has been found to have properties which are different from the naturally occurring (-)-trans-THC. The cannabinoid (-)-cis-THC has been found to occur in low concentrations in particular cannabis plant strains which have been bred to produce cannabidiol (CBD) as the dominant cannabinoid. Furthermore, the cannabinoid can be produced by synthetic means.

The present application discloses powder and aqueous formulations. These include but are not limited to water dispersible cannabinoid formulations, especially those comprising cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) as well as other cannabinoids. Generally, these embodiments do not include major amounts of Tetrahydrocannabinol (THC), but certain embodiments are envisioned that do contain measurable concentrations of THC. Embodiments may include one or more emulsifiers selected from the group consisting of Tween (polysorbate) 20, Tween 60, Tween 80, Span 20, Span 60, Span 80, Poloxamer 188, Vit E-TPGS (TPGS), TPGS-1000, TPGS-750-M, Solutol HS 15, PEG-40 hydrogenated castor oil, PEG-35 Castor oil, PEG-8-glyceryl capylate/caprate, PEG-32-glyceryl laurate, PEG-32-glyceryl palmitostearate, Polysorbate 85, polyglyceryl-6-dioleate, sorbitan monooleate, Capmul MCM, Maisine 35-1, glyceryl monooleate, glyceryl monolinoleate, PEG-6-glyceryl oleate, PEG-6-glyceryl linoleate, oleic acid, linoleic acid, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyglyceryl-3 diisostearate and lecithin.

Cannabis is a plant with an astonishing ability to biosynthesize cannabinoids, and more than 100 molecules belonging to this class have been isolated. Among them in recent years cannabidiol (CBD) has received the interest of pharmacology as the major nonpsychotropic cannabinoid with many potential clinical applications. Although the reactivity of CBD has been widely investigated, only little attention has been given to the possible photodegradation of this cannabinoid, and the data available in the literature are outdated and, in some cases, conflicting. The aim of the present work is providing a characterization of the photochemical behavior of CBD in organic solvents, through a detailed GC-MS analyses, isolation, and NMR characterization of the photoproducts obtained.

Disclosed herein is a method for converting tetrahydrocannabinolic acid (THCA) to cannabinolic acid (CBNA). The method comprises contacting an input material comprising THCA with a benzoquinone reagent under reaction conditions comprising: (i) a reaction temperature that is within a target reaction-temperature range; and (ii) a reaction time that is within a target reaction-time range, to provide an output material in which at least a portion of the THCA from the input material has been converted into CBNA.

A solvent-free method for converting CBD or delta-9 THC-A to delta-9 THC and delta-8 THC includes adding CBD to a reaction vessel, streaming an inert gas through the reaction vessel, heating the CBD while stirring to melt the CBD, stirring the melting CBD, adding concentrated hydrochloric acid as a catalyst to the melting CBD while stirring, increasing the temperature over time to a temperature not to exceed the boiling point of reactants and products in the reaction vessel, holding the reaction vessel at a temperature less than the boiling point temperature for the reactants and products in the reaction vessel for an amount of time to allow the complete conversion of the CBD, and bubbling an inert gas into the reaction products to remove free ions of hydrogen and chloride. The CBD can be replaced in whole or in part by delta-9 THC-A as the reactant.

The present disclosure relates to new cannabinoid sulfonate esters and processes for their use to prepare cannabinoids. The disclosure also relates to the use of catalysts and catalytic processes for the preparation of cannabinoids from the cannabinoid sulfonate esters.

The present invention provides simple synthetic routes for the preparation of cannabinoid compounds such as CBD, CBDV, THC, THCV, CBN, HU-308, CBG, CBC, and derivatives thereof, which are stereoselective and provide the desired cannabinoid compound in high yield.

There is provided the use of extracted active/functional thylakoid membranes from photosynthetic organisms, particularly as vesicles for the formulation of liposoluble compounds such as, for example, THC and other cannabinoids extracted from cannabis. There is further provided a composition in pharmaceutical application, useful for the treatment or prevention of various conditions that may be addressed by cannabinoids (Cbs), made bioavailable or potentiated via formulation in thylakoid membranes. Method for the production thereof are also provided.

Disclosed are methods for separating, recovering, and purifying tetrahydrocannabinolic acid (THCA) salts from an organic solvent solution comprising a mixture of cannabinoids. The methods comprise solubilizing the mixture of cannabinoids in a selected C5-C7 hydrocarbon solvent, adding thereto a selected amine to thereby precipitate a THCA-amine salt therefrom, dissolving the recovered THCA-amine salt in a selected solvent and then adding thereto a selected antisolvent to thereby recrystallize a purified THCA-amine salt therefrom. The recrystallized THCA-amine salt may be decarboxylated to form a mixture of Δ9-tetrahydrocannabinol (Δ9-THC) and amine. The Δ9-THC amine mixture may be acidified to separate the amine from Δ9-THC. The recovered Δ9-THC may be concentrated to produce a highly purified Δ9-THC. Also disclosed are THCA-amine salts produced with amines selected from groups of diamines, amino alcohols, and tertiary amines.

The present invention is directed to methods of producing THC from CBD utilizing non-harsh methodology and resulting in substantially increased yields, as well as devices built upon these novel methods. The methods and devices are material efficient, and in certain embodiments, solvent-free. In particular, in certain embodiments, these methods and related devices are suitable for commercial production of THC from CBD. Furthermore, in certain embodiments, the present invention provides methods of producing THC from CBD in manner that affords tunability to select the ratio of THC -8 to THC-9.

Disclosed herein is a method for converting cannabidiol (CBD) into a composition comprising Δ9-tetrahydrocannabinol ( Δ9-THC) and Δ8-tetrahydrocannabinol ( Δ8-THC) in which the composition has a Δ9-ΤΗΟ: Δ8-ΤΗΟ ratio of greater than 1.0:1.0. The method comprises contacting the CBD with a Lewis-acidic heterogeneous reagent under reaction conditions comprising: (i) an aprotic-solvent system; (ii) a reaction temperature that is less than a threshold reaction temperature for the Lewis-acidic heterogeneous reagent and the aprotic-solvent system; and (ill) a reaction time that is less than a threshold reaction time for the Lewis-acidic heterogeneous reagent, the aprotic-solvent system, and the reaction temperature. Methods for converting CBD into a composition comprising Δ9-THC and Δ8-THC in which the composition has a Δ9-THC: Δ8-THC ratio of greater than 1.0:1.0 under neat reaction conditions are also provided.

Disclosed herein is a method for converting a first cannabinoid into a composition comprising a second cannabinoid and a third cannabinoid, in which the second cannabinoid and the third cannabinoid are each isomers of the first cannabinoid. The composition has a second cannabinoid:third cannabinoid ratio of greater than 1.0:1.0. The method comprises contacting the first cannabinoid with a Lewis-acidic heterogeneous reagent under reaction conditions comprising: (i) a protic-solvent environment, an aprotic-solvent environment, or a solvent-free environment; (ii) a reaction temperature that is within a target reaction-temperature range for the Lewis- acidic heterogeneous reagent and the solvent/solvent free environment; and (iii) a reaction time that is within a target reaction-time range for the Lewis-acidic heterogeneous reagent, the solvent/solvent-free environment, and the reaction temperature.

Disclosed herein is a method for converting cannabidiol (CBD) into a composition comprising Δ9-tetrahydrocannabinol (Δ9-THC) and Δ8-tetrahydrocannabinol (Δ8-THC) in which the composition has a Δ9-ΤΗC:Δ8-ΤΗC ratio of greater than 1.0:1.0. The method comprises contacting the CBD with a Lewis-acidic heterogeneous reagent under reaction conditions comprising: (i) a protic-solvent system; (ii) a reaction temperature that is less than a threshold reaction temperature for the Lewis-acidic heterogeneous reagent and the protic-solvent system; and (ill) a reaction time that is less than a threshold reaction time for the Lewis-acidic heterogeneous reagent, the protic-solvent system, and the reaction temperature.

Disclosed herein a method for converting (cannabidiol) CBD into a composition comprising Δ8-tetrahydrocannabinol (A8-THC) and Δ9-tetrahydrocannabinol (Δ9-THC), in which the composition has a Δ8-THC:Δ9-THC ratio that is greater than 1.0:1.0. The method comprises contacting the CBD with a Lewis-acidic heterogeneous reagent under protic, aprotic, or neat reaction conditions comprising: (i) a reaction temperature that is greater than a threshold reaction temperature for the Lewis-acidic heterogeneous reagent and the solvent system; and (ii) a reaction time that is greater than a threshold reaction time for the Lewis-acidic heterogeneous reagent, the solvent system, and the reaction temperature.

A process for the preparation of substantially pure diverse known and novel cannabinoids 1 and 2, which include Δ9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogues, via intermediates 3, 6, 4 and 5, using a cascade sequence of allylic rearrangement, aromatization and, for the tetracyclic cannabinoids, further highly stereoselective and regioselective cyclization. These synthesized cannabinoids can more easily be obtained at high purity levels than cannabinoids isolated or synthesized via known methods. The cannabinoids 2, including Δ9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), are obtained containing very low levels of isomeric cannabinoids such as the undesirable Δ8- tetrahydrocannabinol. The known and novel analogues with variation in aromatic ring substituents, whilst easily synthesized with the new methodology, would be much more difficult to make from any of the components of cannabis or cannabis oil.

The present invention provides methods of extraction of at least one cannabinoid from an initial cannabis biomass in "one-pot" step using toluene to form a toluene extract and using the toluene extract for producing high concentrations of Δ-9- tetrahydrocannabinol (A9THC) and/or cannabinol (CBN) of a purity of at least 75% and at a yield of at least 75% by weight of the at least one cannabinoid from the initial cannabis biomass in the toluene extract.

The invention discloses a preparation method of delta-9 tetrahydrocannabinol, which comprises the following steps: carrying out esterification on a diol compound represented by formula III and acyl chloride (Cl-R1) to obtain a compound represented by formula IV, carrying out Lewis acid catalysis on the compound represented by formula IV and oleyl alcohol, and reacting in an aprotic solvent to obtain delta-9 tetrahydrocannabinol represented by formula I. According to the method disclosed by the invention, a proper lewis acid use equivalent, a proper reaction temperature and a proper solvent areadopted, the reaction can be quickly completed, and high-purity delta-9 tetrahydrocannabinol can be obtained at a high yield through simple purification.

Enantioselective syntheses of (-)-Δ8-tetrahydrocannabinol ((-)-Δ8-THC) and (-)-Δ9-THC have been achieved in eight and 10 steps, respectively, from a known cinnamic acid. The syntheses take advantage of an enantioselective

Provided are synthesis processes and intermediates for preparing cannabinoids and analogs.

method for decarboxylating a carboxylated phytocannabinoid compound of Formula I to form a phytocannabinoid compound of Formula II: Formula I Formula II wherein: R1 is selected from the group consisting of: substituted or unsubstituted C1-C5 alkyl; R2 is selected from the group consisting of: OH or O, and R3 is selected from the group consisting of: a substituted or unsubstituted cyclohexene, a substituted or unsubstituted C2-C8 alkene, or a substituted or unsubstituted C2-C8 dialkene; or R2 is O, and R2 and R3 together form a ring structure in which R2 is an internal ring atom; wherein the method includes heating a reaction mixture comprising the carboxylated phytocannabinoid compound and a polar aprotic solvent in the presence of a LiCl for a time sufficient to decarboxylate at least a portion of the carboxylated phytocannabinoid compounds and form the phytocannabinoid compound.

A mixture of cannabinoids, drying agents, flowing agents, and/or stabilization agents are provided. The mixture may be a dry powder formulation similar to the consistency of flour or sand. The mixture may comprise a cannabinoid raffinate, an isolated cannabinoid, maltodextrin, and or silica. The ratio of raffinate to solids may be less than 0.625.

A practical synthetic approach to Δ9-tetrahydrocannabinol (1) and cannabidiol (2) that provides scalable access to these natural products and should enable the generation of novel synthetic analogues is reported.

A method for the extraction and isolation of the terpene and isoprenoid compounds from plant material, followed by a centrifugal force induced selective crystallization of isoprenoids resulting in a separation of terpene and isoprenoid fractions. This this method is suitable for the extraction of cannabinoids from Cannabis and the enrichment tetrahydrocannabinolic acid and reduction of tetrahydrocannabinol in an extract. The purity of tetrahydrocannabinolic acid resulting from centrifugal crystallization is such that dissolution and selective recrystallization of tetrahydrocannabinolic acid is possible resulting in >99.9% pure tetrahydrocannabinolic acid, w/w.

Friedel-Crafts alkylation of resorcinols with (S)-cis-verbenol and subsequent cyclization allows the construction of the tetrahydrodibenzopyran core of (-)-δ8-THC which is also found in other natural products in one step. Using a benzofuryl sub

A food additive comprising cannabinoids but lacking at least in part the taste and aroma associated with cannabis while retaining the psychoactive and medicinal properties thereof is provided for as well as methods of making.

The present invention relates to methods for purifying one or two cannabinoid compounds using simulated moving bed chromatography, wherein the cannabinoid compound(s) is/are obtained in the extract and/or the raffinate with the total amount of isomeric impurities being below detection level. In particular, the present invention relates to methods for the purification of cannabidiol, trans-(-)-delta-9-tetrahydrocannabinol, cannabidivarin, trans-(-)-delta-9-tetrahydrocannabivarin and cannabigerol which have been obtained by enantiopure synthesis.

Δ9-THC acid is extracted from cannabis flowers using a first organic solvent, then separated using a second aqueous solvent. Δ9-THC acid is converted to Δ9-THC carboxylic salt before being extracted by a third organic solvent and converted back to Δ9-THC carboxylic acid. Using a solvent swap, Δ9-THC carboxylic acid is decarboxylated and extracted again with an organic solvent prior to purification to give Δ9-THC.

Specific compositions comprising one or multiple (cannabinoid) compound(s) of formula (A) and/or one or multiple salt(s) thereof are described as well as methods for their manufacture. A compound of formula (A), a salt of formula (A) and a respective composition for use as medicine and for use in a method for the therapeutic treatment of the human or animal body, respectively, are also described. Furthermore, corresponding pharmaceutical formulations, cosmetic preparations and foodstuff and/or gourmet or snack preparations fit for consumption as well as a method for the manufacture of delta-9-tetrahydrocannabinol are described.

A simple, highly diastereoselective, Lewis acid catalyzed Friedel-Crafts coupling of a cyclic allylic alcohol with resorcinol derivatives has been developed. The method was applied for the enantiospecific total syntheses of structurally diverse natural products such as machaeriol-D, Δ8-THC, Δ9-THC, epi-perrottetinene and their analogues. Synthesis of both natural products and their enantiomers has been achieved with high atom economy, in a protecting group free manner and in less than 6 steps, the longest linear sequence, in a very good overall yield starting from R-(+) and S-(-)-limonene.

All four stereoisomers of Δ9-tetrahydrocannabinol (Δ9-THC) were synthesized in concise fashion using stereodivergent dual catalysis. Thus, following identical synthetic sequences and applying identical reaction conditions to the same

The highly efficient asymmetric total syntheses of (-)-Δ8- tetrahydrocannabinol ((-)-Δ8-THC) (13 steps, 35%) and (-)-Δ9-tetrahydrocannabinol ((-)-Δ9-THC) (14 steps, 30%) have been developed by using ruthenium-ca

Diels-Alder reactions of a range of 1-(alkoxy/alkyl-substituted phenyl)buta-1,3-dienes with methyl vinyl ketone and methyl acrylate carried out in ethanol as the reaction medium under 9 kbar pressure were investigated. The use of high pressure as the activating method of the Diels-Alder reactions allows the efficient and endodiastereoselective generation of a series of cis-cyclohexenyl-benzene cycloadducts, which are selectively converted into their trans-epimers. The cis-cyclohexenyl-benzenes and trans-cyclohexenyl- benzenes produced are useful precursors for accessing substituted privileged cis-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene and trans-6a,7,8,10a-tetrahydro- 6H-benzo[c]chromene skeletons. The total syntheses of Δ9-cis- tetrahydrocannabinol (THC) and Δ9-trans-THC, through the use of selected Diels-Alder adducts, are described. Finally, a route for obtaining Δ9-trans-THC in both enantiomeric pure forms based on the (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP)-hydrazone method is also reported.

The present disclosure is directed to a process for the chemical synthesis of (-)-Δ9- ^tetrahydrocannabinol (Δ9-THC) and related compounds of formula (I). In particular, the process comprises a one-pot condensation and sulfonylatton

Disclosed herein are heat-labile prodrugs, their preparation and uses.

(Chemical Equation Presented) Δ9-THC is synthesized in enantiomericaly pure form, where all of the stereochemistry is derived from the molybdenum-catalyzed asymmetric alkylation reaction of the extremely sterically congested bis-ortho-substitut

Marijuana abuse continues to plague society and the lack of effective treatments warrants concern. Catalytic antibodies capable of oxidatively degrading the major psychoactive component of marijuana, Δ9- tetrahydrocannabinol (Δ9-THC), are presented. The antibodies generate reactive oxygen species from singlet oxygen (1O 2*), using riboflavin (vitamin B2) and visible light as the 1O2*source. Cannabitriol was identified as the major degradation product of this reaction, demonstrating the ability of an antibody to catalyze a complex chemical transformation with therapeutic implications for treating marijuana abuse.

Pharmaceutical compositions comprising the cannabinoid active pharmaceutical ingredient, crystalline trans-(±)-Δ9-tetrahydrocannabinol, and formulations thereof are disclosed. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of crystalline trans-(±)-Δ9-tetrahydrocannabinol. In specific embodiments, the crystalline trans-(±)-Δ9-tetrahydrocannabinol administered according to the methods for treating or preventing a condition such as pain can have a purity of at least about 98% based on the total weight of cannabinoids.

The present invention relates to a method for the production of dronabinol ((6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H- dibenzo[b,d]pyran-1-ol, Δ9-tetrahydrocannabinol (Δ9-THC)) from cannabidiol (CBD) by the cyclisation of cannabidiol (CBD) (2-[1 R-3-methyl-6-(1-methylethenyl)-2-cyclohexen-1-yl]-5-pentyl-1,3-benzoldiol) to Δ9-THC. The method according to the invention is characterised in that cannabidiol (CBD) is provided in an organic solvent and is cyclised to Δ9-THC by heating, in the presence of a molecular sieve. It was ascertained that, in the method according to the invention, in addition to the previously described drying properties, the molecular sieve also has good catalytic properties, which play an important part in the above reaction. As a rule, cyclisation carried out in the presence of a Lewis acid catalyst alone is markedly slower and yields less Δ9-THC than cyclisation carried out in the presence of a molecular sieve.

The invention relates to a method for obtaining pure tetrahydrocannabinol from reaction mixtures containing tetrahydrocannabinol compounds or from raw products containing tetrahydrocannabinol compounds. According to said method, the tetrahydrocannabinol compounds in the reaction mixture or in the raw product are converted into crystallisable derivatives, preferably using a suitable solvent, said derivatives are then crystallised and isolated, and the pure tetrahydrocannabinol compounds are then obtained from the crystallised derivatives. The invention also relates to the use of compounds produced in this way for the production of a medicament for human therapy, and to the medicaments thus produced.

Methods for making trans-(-)-Δ9-tetrahydrocannabinoI and trans-(+)-Δ9-tetrahydrocannabinol are disclosed herein. In one embodiment, a trans-(-)-Δ9-tetrahydrocannabinoI composition is prepared by allowing a composition comprising (±)-Δ9-tetrahydrocannabinol to separate on a chiral stationary phase to provide a trans-(-)-Δ9-tetrahydrocannabinoI composition comprising at least about 99% by weight of trans-(-)-Δ9-tetrahydrocannabinol based on the total amount of trans-(-)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of a trans-(-)-Δ9-tetrahydrocannabinoI having a purity of at least about 98% based on the total weight of cannabinoids.